Clan type peptidase | M04.001 - thermolysin (Bacillus thermoproteolyticus), MEROPS Accession MER0001026 (peptidase unit: 233-548); PDB accession 1TLP |
History | Biochem.J. 290:205-218 (1993) |
Description | Water nucleophile; water bound by single zinc ion ligated to two His (within the motif HEXXH) and Glu, His or Asp |
Contents of clan | Clan MA contains a variety of metallopeptidases. |
Evidence | The families in clan MA are united by the presence of an HEXXH motif in which the two His residues are zinc ligands and the Glu has a catalytic function. The motif HEXXH occurs in non-peptidase proteins too, but a more specific motif can be defined for clan MA. This larger motif is Xaa-Xbb-Xcc-His-Glu-Xbb-Xbb-His-Xbb-Xdd in which Xaa is hydrophobic or Thr, Xbb is uncharged, Xcc is any amino acid except Pro, and Xdd is hydrophobic (Jongeneel et al., 1989). There is a third zinc ligand towards the C-terminus, and the nature of this varies with the subclan (see below). |
Catalytic mechanism | The mechanism of catalysis by metallopeptidases in clan MA has been reviewed by Auld (2004). |
Peptidase activity | Types of peptidase activity include aminopeptidase (in families M1, M61), carboxypeptidase (M2, M32), peptidyl-dipeptidase (M2), oligopeptidase (M3, M13) and endopeptidase (families M4, M10, M12 and others). The matrix metallopeptidases in family M10 and the ADAM peptidases and snake venom metallopeptidases in family M12 have been subjects of particularly intense research. |
Protein fold | The molecule of snapalysin (M07.001) illustrates the minimal structure of the peptidase unit in clan MA. The snapalysin molecule contains a bundle of helices and a Greek key-like beta sheet, with the active site located between two helices (Kurisu et al., 1997). This general structure is common to all members of clan MA, but frequently a more elaborate second domain replaces the single helix that forms half of the active site in snapalysin; for example, in thermolysin (M04.001) the second domain is a bundle of five helices (Matthews et al., 1972). The molecules of most peptidases in clan MA contain non-peptidase domains as well as the peptidase unit. |
Homologous non-peptidase families | The fold is largely confined to members of clan MA. A protein of unknown function from Aquifex aeolicus has a similar fold and may prove to represent a new family of metallopeptidases (Oganesyan et al., 2003). |
Activation mechanism | Some of the endopeptidases in subclan MA(E) are synthesised as proenzymes that are activated by removal of an N-terminal propeptide (e.g. pseudolysin, M04.005: Kessler & Safrin, 1994). The peptidases in subclan MA(M) are synthesised as inactive proenzymes. In some, the inactivity of the proenzyme is attributable to an interaction between a conserved Cys in the propeptide and the catalytic zinc ion that prevents the binding of a water molecule. This "cysteine switch" mechanism (Van Wart & Birkedal-Hansen, 1990) is found in families M8, M10 subfamily A, M11 and M12 subfamily B. Almost without exception, peptidases in subclan MA(M) that lack the cysteine switch contain a catalytically-important Tyr two residues beyond the Met of the Met-turn (see the Alignment for subclan MA(M)). |
Other databases
| PFAM | CL0126 |
| SCOP | 55486 |
M06 |
immune inhibitor A peptidase ({Bacillus} sp.) (Bacillus thuringiensis) |
- |
M07 |
snapalysin (Streptomyces lividans) |
Yes |
M35 |
deuterolysin (Aspergillus flavus) |
Yes |
M41 |
FtsH peptidase (Escherichia coli) |
Yes |
M64 |
IgA peptidase ({Clostridium ramosum}-type) (Clostridium ramosum) |
- |
M01 |
aminopeptidase N (Homo sapiens) |
Yes |
M02 |
angiotensin-converting enzyme peptidase unit 1 (Homo sapiens) |
Yes |
M03 |
thimet oligopeptidase (Rattus norvegicus) |
Yes |
M04 |
thermolysin (Bacillus thermoproteolyticus) |
Yes |
M05 |
mycolysin (Streptomyces cacaoi) |
- |
M09 |
collagenase V ({Vibrio} spp.) (Vibrio alginolyticus) |
Yes |
M100 |
spartan peptidase (Homo sapiens) |
- |
M101 |
flagellinolysin (Clostridium haemolyticum) |
- |
M102 |
DA1 peptidase ({Arabidopsis thaliana}) (Arabidopsis thaliana) |
- |
M106 |
FP0506 g.p. ({Flavobacterium psychrophilum}) (Flavobacterium psychrophilum) |
- |
M13 |
neprilysin (Homo sapiens) |
Yes |
M26 |
IgA1-specific metallopeptidase (Streptococcus sanguinis) |
- |
M27 |
tentoxilysin (Clostridium tetani) |
Yes |
M30 |
hyicolysin (Staphylococcus hyicus) |
- |
M32 |
carboxypeptidase Taq (Thermus aquaticus) |
Yes |
M34 |
anthrax lethal factor (Bacillus anthracis) |
Yes |
M36 |
fungalysin (Aspergillus fumigatus) |
- |
M48 |
Ste24 peptidase (Saccharomyces cerevisiae) |
Yes |
M49 |
dipeptidyl-peptidase III (Rattus norvegicus) |
Yes |
M56 |
BlaR1 peptidase (Staphylococcus aureus) |
- |
M60 |
enhancin (Lymantria dispar nucleopolyhedrovirus) |
- |
M61 |
glycyl aminopeptidase (Sphingomonas capsulata) |
- |
M76 |
Atp23 peptidase (animal-type) (Homo sapiens) |
- |
M78 |
ImmA peptidase (Bacillus subtilis) |
- |
M85 |
NleC peptidase ({Escherichia coli}) (Escherichia coli) |
- |
M87 |
chloride channel accessory protein 1 (Homo sapiens) |
- |
M88 |
IMPa peptidase ({Pseudomonas aeruginosa}) (Pseudomonas aeruginosa) |
- |
M90 |
MtfA peptidase (Escherichia coli) |
Yes |
M91 |
NleD peptidase ({Escherichia coli}-type) (Escherichia coli) |
- |
M93 |
BACCAC_01431 g.p. ({Bacteroides caccae}) and similar (Bacteroides caccae) |
- |
M95 |
abylysin ({Pyrococcus abyssi}) (Pyrococcus abyssi) |
- |
M98 |
YghJ g.p. ({Escherichia coli}) (Escherichia coli) |
- |
M08 |
leishmanolysin (Leishmania major) |
Yes |
M10 |
matrix metallopeptidase-1 (Homo sapiens) |
Yes |
M105 |
MAP1 peptidase ({Myxococcus xanthus}, {Pimelobacter} sp.) (Myxococcus xanthus) |
- |
M11 |
gametolysin (Chlamydomonas reinhardtii) |
- |
M12 |
astacin (Astacus astacus) |
Yes |
M43 |
cytophagalysin (Cytophaga sp.) |
Yes |
M54 |
archaelysin (Methanocaldococcus jannaschii) |
- |
M57 |
prtB g.p. ({Myxococcus xanthus}) (Myxococcus xanthus) |
- |
M66 |
StcE peptidase (Escherichia coli) |
- |
M72 |
peptidyl-Asp metallopeptidase (Pseudomonas aeruginosa) |
- |
M80 |
Wss1 peptidase ({Saccharomyces}-type) (Saccharomyces cerevisiae) |
- |
M84 |
MpriBi peptidase ({Bacillus} sp.) (Bacillus intermedius) |
- |
M97 |
EcxAB peptidase (Escherichia coli) |
- |